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Biomedical subjects

M W Lingen

Publications and source records attributed to M W Lingen.

At least 19 recordsLinked to original sources
PubMed2006

Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation.

Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, agents that inhibit angiogenesis have important therapeutic implications in numerous malignancies. We examined the effects of methylnaltrexone (MNTX), a peripheral mu opioid receptor antagonist, on agonist-induced human EC proliferation and migration, two key components in angiogenesis. Using human dermal microvascular EC, we observed that morphine sulfate (MS), the active metabolite, morphine-6-glucuronide (M6G), DAMGO ([d-Ala(2), N-Me-Phe(4), Gly(5)-ol]enkaphalin) and VEGF induced migration which were inhibited by pretreatment with MNTX at therapeutically relevant concentration (0.1 microM). The biologically inactive metabolite morphine-3-glucuronide (M3G) did not affect EC migration. We next examined the mechanism(s) by which MNTX inhibits opioid and VEGF-induced angiogenesis using human pulmonary microvascular EC. MS and DAMGO induced Src activation which was required for VEGF receptor transactivation and opioid-induced EC proliferation and migration. MNTX inhibited MS, DAMGO and VEGF induced tyrosine phosphorylation (transactivation) of VEGF receptors 1 and 2. Furthermore, MS, DAMGO and VEGF induced RhoA activation which was inhibited by MNTX or VEGF receptor tyrosine kinase inhibition. Finally, MNTX or silencing RhoA expression (siRNA) blocked MS, DAMGO and VEGF-induced EC proliferation and migration. Taken together, these results indicate that MNTX inhibits opioid-induced EC proliferation and migration via inhibition of VEGF receptor phosphorylation/transactivation with subsequent inhibition of RhoA activation. These results suggest that MNTX inhibition of angiogenesis can be a useful therapeutic intervention for cancer treatment.

Angiogenesis Inhibitors↗
PubMed2006

NOL7 is a nucleolar candidate tumor suppressor gene in cervical cancer that modulates the angiogenic phenotype.

Cervical cancer is associated with human papilloma virus infection. However, this infection is insufficient to induce transformation and progression. Loss of heterozygosity analyses suggest the presence of a tumor suppressor gene (TSG) on chromosome 6p21.3-p25. Here we report the cloning NOL7, its mapping to chromosome band 6p23, and localization of the protein to the nucleolus. Fluorescence in situ hybridization analysis demonstrated an allelic loss of an NOL7 in cultured tumor cells and human tumor samples. Transfection of NOL7 into cervical carcinoma cells inhibited their growth in mouse xenografts, confirming its in vivo tumor suppressor activity. The induction of tumor dormancy correlated with an angiogenic switch caused by a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These data suggest that NOL7 may function as a TSG in part by modulating the expression of the angiogenic phenotype.

Animals↗
PubMed2004

Differential expression of the non-receptor tyrosine kinase BRK in oral squamous cell carcinoma and normal oral epithelium.

BRK is a non-receptor tyrosine kinase whose functional role is poorly understood. Although it is an epithelial specific kinase, its expression appears to be tissue specific. To date, little is known about BRK expression in human oral epithelium. We investigated expression of BRK in human oral squamous cell carcinomas (OSCC) and normal oral epithelium (NOE) using immunohistochemistry, laser confocal microscopy and Western blotting. The subcellular localization of BRK was identified by confocal microscopy and Western blotting of nuclear and cytoplasmic extracts from these cells. The results indicate that NOE express higher levels of BRK compared with OSCC cells. In NOE and moderately differentiated OSCC cells, BRK was localized in the nucleus and cytoplasm. However, in poorly differentiated OSCC cells, BRK was localized in perinuclear regions. These results suggest that BRK expression differs in normal and OSCC which may reflect a possible functional involvement in OSCC.

Blotting, Western↗
PubMed2001

Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid.

Recent studies indicate that angiogenesis is important in the pathogenesis of leukemias, apart from its well-established role in solid tumors. In this study, the possible role of angiogenesis in acute promyelocytic leukemia (APL) was explored. Bone marrow trephine biopsies from patients with APL showed significantly increased microvessel density and hot spot density compared with normal control bone marrow biopsies. To identify the mediators of angiogenesis in APL, quantitative and functional assays were performed using the NB4 APL cell line as a model system. Conditioned media (CM) from the NB4 cells strongly stimulated endothelial cell migration. CM from the NB4 cells contained high levels of vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor (bFGF). Most important, the addition of neutralizing VEGF antibodies completely inhibited the ability of NB4 CM to stimulate endothelial cell migration, suggesting that APL angiogenesis is mediated by VEGF. The effect of all-trans retinoic acid (ATRA) on APL angiogenesis was then studied. ATRA therapy resulted in a decrease in bone marrow microvessel density and hot spot density. CM from ATRA-treated APL cells did not stimulate endothelial cell migration. Finally, quantitative assays showed that ATRA treatment resulted in the abrogation of VEGF production by the NB4 cells. These results show that there is increased angiogenesis and VEGF production in APL and that ATRA therapy inhibits VEGF production and suppresses angiogenesis. The addition of specific antiangiogenic agents to differentiation therapy or chemotherapy should be explored. (Blood. 2001;97:3919-3924)

Bone Marrow↗
PubMed2001

Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages.

Angiogenesis, an essential step in the development of neoplasia, is a complex process that involves the interaction of tumor cells with stromal cells. Tumor-associated macrophages (TAMs) can participate in the induction of tumor angiogenesis and are thought to be of prognostic value in some neoplasms. We have investigated how macrophages contribute to angiogenesis in head-and-neck squamous-cell carcinoma (HNSCC) and have found that tumor cells attract monocytes and activate them to secrete angiogenic factors. The attraction of macrophages was due to the secretion of monocyte chemotactic protein-1 and TGF-beta1 by tumor cells, while tumor production of TGF-beta1 was responsible for activating macrophages. In addition, activated macrophages produced cytokines that acted in a paracrine fashion by secreting both TNF-alpha and IL-1, which in turn stimulated tumor cells to secrete increased levels of IL-8 and VEGF. These data demonstrate that TAMs play an important role in the in vivo induction of angiogenesis in HNSCC and suggest that anti-angiogenic therapies for HNSCC and perhaps other neoplasms must include strategies that will block the ability of tumor cells to recruit macrophages into the tumor micro-environment.

Animals↗
PubMed2001

Role of leukocytes and endothelial cells in the development of angiogenesis in inflammation and wound healing.

The basic signs and symptoms of inflammation and wound healing have been appreciated for thousands of years. However, the specific cells involved and their roles in this complex environment are still being elucidated today. In 1926, the origin of the phagocytic mononuclear ameboid wandering cell (macrophage) had not been determined. One popular theory was that the cells were differentiated from the endothelial cells of the nearby blood vessels, whereas others believed that the cells came from the peripheral blood or resting wandering cells. The purpose of this article is to review the seminal article published by Lang regarding this topic nearly 75 years ago. In addition, this article will review what is now known with regard to the role of the macrophage and endothelial cells in the development of angiogenesis, which is arguably the most critical component of successful inflammatory process or wound healing.

Animals↗
PubMed2001

Angiogenesis in oral cancer.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy that develops after years of chronic exposure to alcohol and tobacco products. Exposure to these agents results in alterations of genes that are important in the regulation of various cellular functions. This loss of regulation allows the tumor cells to survive and grow in an unchecked manner by allowing the cells to perform functions that contribute to the growth of the tumor. Some of these important changes include the acquisition of immortality and the ability to invade tissue and/or metastasize to other sights, as well as acquiring the ability to induce angiogenesis. Angiogenesis, the growth of new blood vessels from pre-existing ones, is a complex phenomenon that is absolutely required for the continued growth and survival of solid neoplasms. Without new blood vessels to provide nutrients and remove waste, tumors would be unable to grow larger than 2-3 mm in diameter. Therefore, one could envision its potential role in both the treatment and prevention of malignancies such as HNSCC. The concept of chemoprevention is extremely important in HNSCC since patients often develop multiple independent lesions throughout the mucosa of the upper aerodigestive tract. Therefore, the comprehensive treatment of this disease must address not only the initial primary neoplasm, but also prevent the progression of the premalignant lesions lurking throughout the rest of the mucosal surfaces. This review will outline the basic changes that occur in tumor cells that result in the switch to angiogenic phenotype. In addition, it will discuss the present status of using antiangiogenic agents in the treatment of cancer. Finally, this paper will present a rationale for the use of multiple antiangiogenic agents as a means of developing new chemotherapeutic and chemopreventive protocols that may result in reduced patient toxicity while maintaining similar clinical efficacies.

Angiogenesis Inhibitors↗
PubMed2000

Overexpression of p53 in squamous cell carcinoma of the tongue in young patients with no known risk factors is not associated with mutations in exons 5-9.

BACKGROUND: This study investigated the status of the p53 tumor suppressor gene in patients less than 40 years of age who had squamous cell carcinoma of the tongue develop with no known risk factors. METHODS: Histologic sections from 21 patients were prepared from formalin-fixed, paraffin-embedded tissue and were processed for standard immunohistochemistry for detection of the p53 protein. In addition, tumors were evaluated by single-strand conformation polymorphism and by DNA sequencing to identify potential mutations in the conserved exons (5-9) of the p53 gene. RESULTS: Eighty-one percent (17 of 21) of the patients overexpressed p53 by immunohistochemical analysis. However, none of these patients demonstrated mutations in exons 5-9 of the gene. CONCLUSIONS: These data suggest that the molecular mechanisms by which the young individuals with no risk factors had altered p53 function in oral squamous cell carcinoma may differ from those of the more typical population of individuals who have this malignancy develop.

Adolescent↗
PubMed2000

Effect of alendronate on immature human dental root explants.

This study investigated the use of alendronate in the formation of new dentin in vitro. Extracted human premolar and molar teeth with immature apices were grown in tissue culture medium for 60 days. Six control specimens were grown without alendronate in the medium, and 22 experimental specimens were grown with alendronate at [10(-9) M] in the medium. Newly formed dentin was stained with tetracycline and procion brilliant red at days 1 to 3, 30 to 33, and 60. Specimens were decalcified and 5-micron sections were prepared for examination using fluorescent microscopy. New dentin formation was measured in microns at the most apical region, at 125-micron from the apical measurement and at 250-micron from the apical measurement. The alendronate group had 57.15% more growth than the control group at the most apical region, and this difference was significant (p = 0.0001). The results indicate that alendronate at [10(-9) M] is effective in accelerating dentin formation in vitro.

Alendronate↗
PubMed2000

New therapeutic strategies for the treatment and prevention of head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy that is now the sixth most common neoplasm in the world today. Approximately 50,000 cases in the United States and more than 500,000 cases worldwide will be diagnosed in 2000 [1]. Despite numerous advances in treatment utilising the most recent protocols for surgery, radiation and chemotherapy, the long-term survival has remained at less than 50% over the past 40 years [2]. This poor long-term survival is due to a number of variables including delayed diagnosis as well as the frequent development of multiple primary tumours. Therefore, in addition to early detection, continued emphasis must be placed on preventing the development of new primaries as well as establishing more effective treatments for individuals who present with advanced disease. This review will summarise some of the recent advances in the realms of chemotherapy and radiation therapy. In addition, it will discuss the present status of chemoprevention in HNSCC. Finally, we will discuss the rationale for the use of anti-angiogenic agents as one possible means of developing new chemopreventive protocols that result in reduced toxicity while maintaining similar clinical efficacies.

Animals↗
PubMed2000

Acellular dermal matrix allografts to achieve increased attached gingiva. Part 1. A clinical study.

BACKGROUND: Freeze-dried acellular dermal matrix (ADM) allograft, originally used for full-thickness burn wounds, was recently introduced as an alternative to the autogenous free gingival graft (FGG) in achieving increased attached keratinized tissue. The aim of part 1 of this study was to investigate the clinical efficacy of the ADM allograft for this particular purpose. METHODS: Twelve patients, 7 males and 5 females, with attached gingiva < or =1 mm on the facial aspect of mandibular anterior teeth demonstrating a tendency of progressive marginal tissue recession, were randomly assigned to either test or control treatment. Six patients received ADM graft (test) and 6 patients received an autogenous FGG harvested from the hard palate (control). Clinical variables including plaque index (PI), gingival index (GI), probing depth (PD), attached tissue width (AT), and gingival recession (GR) were recorded immediately before surgery and at the 6-month postoperative visit. Patients were seen at 2, 4, 6, 8, and 12 weeks to monitor wound healing and oral hygiene performance (PI and GI). Graft width was also measured, in corono-apical direction, on individually involved teeth during the surgery. RESULTS: When values between baseline and 6 months were compared in both groups, there was no statistically significant difference in changes of PI, GI, PD, and GR (P>0.05) with the exception of PD in the FGG group (1.01 +/- 0.03 versus 1.27 +/- 0.20 mm, P= 0.042). There was a statistically significant (P <0.05) increase in AT in both groups. Although the ADM group received wider grafts than the FGG group (8.81 +/- 0.46 versus 6.70 +/- 0.89 mm), the AT gain was significantly smaller (2.59 +/- 0.92 versus 5.57 +/- 0.44 mm) and the graft shrinkage significantly greater (71 +/- 10% versus 16 +/- 12%) in the ADM group than in the FGG group (P<0.01). CONCLUSIONS: The results of this study suggest that in procedures aiming at increasing the width of attached gingiva: 1) the ADM allograft was less effective and less predictable than the autogenous FGG in terms of increasing attached keratinized tissue due to considerable shrinkage and inconsistent quality of the attached tissue gained and 2) the esthetic results using the ADM allograft might be better than those using the autogenous FGG.

Adult↗
PubMed1999

Differentiation and the cytomorphology of salivary gland tumors with specific reference to oncocytic metaplasia.

OBJECTIVE: The different cell types and many growth patterns found in salivary gland tumors provide ample reason for the diagnostic problems caused by these tumors. To improve criteria for differential diagnosis, the potential range of cytologic features possible in salivary gland tumor cells must be better appreciated. STUDY DESIGN: From our respective pathology archives, normal salivary tissue and salivary gland tumours--other than Warthin's tumor and oncocytoma--with oncocytic differentiation were identified and studied by means of light and electron microscopy. RESULTS: In this article, we cite a number of different salivary gland tumors, including basal cell adenoma, pleomorphic adenoma, myoepithelioma, polymorphous low-grade adenocarcinoma, and mucoepidermoid carcinoma, showing varying degrees of oncocytic differentiation. CONCLUSIONS: Variable cellular differentiation is probably the basis for foci of tumor cells unexpected for a particular salivary gland neoplasm, further compounding differential diagnosis. Illustration of oncocytic differentiation serves 2 purposes. First, it can alert pathologists to this potential in otherwise typical salivary gland tumors; an awareness of this and other possible variations in cellular differential patterns can help prevent misdiagnosis. Second, these particular tumors illustrate the role of the cellular differentiation that is responsible for the range of histologic features within any one subtype of salivary gland tumors.

Cell Differentiation↗
PubMed1999

Nitric oxide synthase type 3 is increased in squamous hyperplasia, dysplasia, and squamous cell carcinoma of the head and neck.

The implication of nitric oxide (NO*) in the multistep process of carcinogenesis prompted us to examine the expression of endothelial constitutive nitric oxide synthase (NOS3) in head and neck squamous cell carcinoma (HNSCCa). Eleven paraffin-embedded samples of normal oral mucosa, 3 reactive oral lesions, 13 samples of squamous dysplasia, and 120 specimens of HNSCCa were immunostained with an anti-NOS3 monoclonal antibody and graded on a 0 to 4+ scale of intensity. Normal squamous mucosa demonstrated very little NOS3 expression. Areas of normal mucosa, reactive mucosa, and dysplastic lesions associated with inflammation tended to demonstrate regional expression of NOS3. Reactive mucosal lesions, squamous dysplasia, and HNSCCa demonstrated a significant (p<.0001) increase in global expression of NOS3. Therefore, NOS3 is expressed very little in histologically normal squamous mucosa, while squamous hyperplasia, dysplasia, and HNSCCa express significantly more NOS3. Regional variation in NOS3 expression appears to be associated with perilesional inflammation.

Antibodies, Monoclonal↗
PubMed1999

Angiogenesis in the development of head and neck cancer and its inhibition by chemopreventive agents.

Squamous cell carcinoma is an aggressive malignancy that often develops as multiple independent lesions throughout the mucosa of the upper aerodigestive tract. Therefore, the comprehensive treatment of this disease must not only address the initial primary neoplasm, but also prevent the progression of the premalignant lesions lurking throughout the rest of the mucosal surfaces. The need to treat these lesions has resulted in a search for chemopreventive agents that can halt or even reverse their malignant progression. The biologic and molecular mechanisms by which most chemopreventive agents act have remained unclear and controversial. Recent work from several laboratories has demonstrated that some drugs may act in part by inhibiting the ability of tumors to induce blood vessel growth. Angiogenesis, the growth of new blood vessels from pre-existing ones, is absolutely required for solid neoplasms to grow beyond 2-3 mm in diameter. Therefore, chemopreventive agents that act to inhibit angiogenesis may provide a very powerful modality by which one may limit the growth of both pre-malignant lesions and small nests of tumor cells. This review will outline the basic changes that occur in tumor cells that result in the switch from an anti-angiogenic to an angiogenic phenotype. In addition, it will discuss the mechanisms by which some chemopreventive agents, presently under clinical investigation, inhibit tumor angiogenesis. Finally, this paper will present a rationale for the use of multiple anti-angiogenic agents as a means of developing new chemopreventive protocols that result in reduced patient toxicity while maintaining similar clinical efficacies.

Angiogenesis Inhibitors↗
PubMed1998

Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against human head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy in which multiple independent lesions develop over time throughout the mucosa of the upper aerodigestive tract. Therefore, the comprehensive treatment of this neoplasm must include a chemopreventive arm to hold premalignant lesions in check, a role well-suited to antiangiogenic agents. Retinoic acid (RA) and interferon alpha (IFN-alpha), drugs with known biological activity against HNSCC when used individually, are also inhibitors of angiogenesis. Here we show that they are remarkably synergistic antiangiogenic agents able to inhibit both the growth and the neovascularization of HNSCC injected into the floor of the mouth of nude mice. The mechanism of action of these drugs as antiangiogenic agents was 2-fold. They decreased the angiogenic activity of the tumor cells, and they caused the endothelial cells to become refractory to inducers of angiogenesis. When tumor cells were treated in vitro with IFN-alpha A/D, there was a dramatic drop in their secretion of interleukin-8, the major angiogenic factor produced by these tumors. When combined with RA, which causes tumor cells to secrete an inhibitor of angiogenesis, there was a synergistic inhibition of both tumor cell growth and secreted angiogenic activity. The combination of RA and IFN-alpha also acted synergistically on endothelial cells by reducing their responsiveness to both interleukin-8 and tumor conditioned media. Doses of each drug could be reduced by two logs without loss of activity. When animals bearing human HNSCC tumor cells were treated systemically with a combination of RA and IFN-alpha A/D at doses that were ineffective when used alone, dramatic decreases in both tumor growth and tumor angiogenesis were seen. These data suggest that the use of antiangiogenic mixtures may be a particularly effective way to design future chemoprevention protocols against HNSCC.

Animals↗
PubMed1997

The angiogenic switch in hamster buccal pouch keratinocytes is dependent on TGFbeta-1 and is unaffected by ras activation.

This study was undertaken to investigate the mechanisms by which Syrian hamster buccal pouch keratinocytes treated in vivo with 7,12-dimethylbenz[a]anthracene (DMBA), switch from an angio-inhibitory to an angiogenic phenotype. Cells were cultured from pouches at various times after exposure to carcinogen and their angiogenic activity assessed. The angio-inhibitory activity present in conditioned media from normal cells was lost as early as 3 weeks after carcinogen treatment, resulting in weak expression of angiogenic activity. By 5 weeks, cells had become strongly angiogenic due to the secretion of high levels of TGFbeta-1, a potent angiogenic factor. Because the switch to high levels of secreted TGFbeta-1 occurred at the same time as the activation of the H-ras oncogene, non-angiogenic cell lines lacking an activated H-ras oncogene were stably transfected with mutant H-ras and their transformed and angiogenic phenotypes were evaluated. Although ras transfection drove two of the three cultured cell lines to anchorage independence and modestly increased their ability to clone in low serum, it had no effect on the angiogenic phenotype or on the level of secreted active TGFbeta-1. These results demonstrate that the angiogenic phenotype in the hamster buccal pouch model of oral carcinogenesis develops in a step-wise fashion with an early decrease in the production of an inhibitor of angiogenesis and a subsequent marked increase in the secretion of the inducer TGFbeta-1. Although the activation of the H-ras oncogene contributed to anchorage independence, it did not affect the expression of the angiogenic phenotype in this model system.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats.

Captopril, an inhibitor of angiotensin converting enzyme, is widely used clinically to manage hypertension and congestive heart failure. Here captopril is shown to be an inhibitor of angiogenesis able to block neovascularization induced in the rat cornea. Captopril acted directly and specifically on capillary endothelial cells, inhibiting their chemotaxis with a biphasic dose-response curve showing an initial decrease at clinically achievable doses under 10 microM and a further slow decline in the millimolar range. Captopril inhibition of endothelial cell migration was not mediated by angiotensin converting enzyme inhibition, but was suppressed by zinc. Direct inhibition by captopril of zinc-dependent endothelial cell-derived 72-and 92-kD metalloproteinases known to be essential for angiogenesis was also seen. When used systemically on rats captopril inhibited corneal neovascularization and showed the antitumor activity expected of an inhibitor of angiogenesis, decreasing the number of mitoses present in carcinogen-induced foci of preneoplastic liver cells and slowing the growth rate of an experimental fibrosarcoma whose cells were resistant to captopril in vitro. These data define this widely used drug as a new inhibitor of neovascularization and raise the possibility that patients on long term captopril therapy may derive unexpected benefits from its antiangiogenic activities.

Angiotensin-Converting Enzyme Inhibitors↗